Implant having a long-term antibiotic effect

ABSTRACT

The invention relates to an implant with antibiotic long-term action, in particular a vascular prosthesis, with a basic structure which defines the form of the implant and which is made of substantially non-absorbable or only slowly absorbable polymer material and of a coating of an absorbable material, with a layer of metallic silver situated on the polymer material and underneath the coating.

The invention relates to an implant with antibiotic long-term action.Infection following implantation of prostheses and other implants is arisk factor feared by physicians and patients alike. The incidence ofimplant infection is approximately 0.5 to 5%. Risk factors affectingartificial vascular implants are, for example, emergency operations, asubcutaneous position of the prosthesis or, possibly, positioning of theprosthesis in the inguinal region. A distinction is drawn between earlyinfections, which generally occur within a period of up to 4 monthsafter implantation, and so-called late infections which become apparentafter a longer period of time has elapsed since implantation. Clinicalreports confirm, for infections of the aorta for example, an onset after25-70 months. In the aorto-femoral position, the average time untilonset of infection is 41 months. Extracavitary prosthesis infectionsoccur earlier (within 7 months). The microbes which cause suchinfections include, in particular, Staphylococcus aureus, Staphylococcusepidermidis and Escherichia coli. The infection generally results fromintraoperative contamination. However, it can also occur in thepost-operative phase, in particular in the case where the patient has aninfection that has not completely healed. The microbes or microorganismstend to adhere to the prosthesis surface. In doing so, they may form amicrocolony within a biofilm, and in the course of time they may becomesealed off from the outside. Particularly in cases where the patient hasbeen weakened for other reasons, virulent infection and inflammatoryreactions may occur with involvement of the perigraft tissue and theanastomosis regions.

It is known that silver has an antibiotic action. Silver salts andmetallic silver are therefore widely used to combat microorganisms.Thus, it is known, for example from WO 93/07924, for articles made ofplastics, metal and ceramics and introduced into the body, for examplefixation devices, nails, pins, catheters, stents, tracheostomy tubes,shunts, percutaneous connectors, wound drainage devices, dental implantsand the like, to be provided with a bactericidal component, inparticular of platinum, iridium, gold, silver, mercury, copper, iodineand their alloys, compounds and oxides. The corresponding substances areapplied in the form of ionized atoms in a vacuum chamber byion-beam-assisted deposition (IBAD). Biomedical implants with similarbactericidal surfaces are described in U.S. Pat. No. 5,492,763. In thelatter, biomedical articles such as metallic needles, urology catheters,percutaneous clamps and ceramic and metallic countersurfaces of hipjoints and knee joints are mentioned.

From WO 81/02667, it is also known to provide implants, for exampleartificial joints, with a surface coating of silver or silver alloys ina layer thickness of 25 to 500 Å, in order, on the one hand, to avoidbacterial growth and, on the other hand, to ensure that the amount ofsilver is not so great as to damage surrounding connective tissue.

From U.S. Pat. No. 5,464,438 it is also known for metallic gold to bevapor-deposited on implants made of textile material, in order to reducethe risk of thrombosis.

Textile implants, especially when used as replacements for holloworgans, in particular ducts, and chiefly including vascular prostheses,are normally provided with sealing coatings in order to close the poresof the textile prostheses at least initially. It has been proposed toincorporate bactericidal substances into the coating material in orderin this way to be able to avoid infections after implantation. Suchcoatings, which among other things can contain silver ions, are set outin WO 00/32247.

It is an object of the invention to make available an implant, inparticular a vascular prosthesis, with antibiotic long-term action,which implant is to be able to be handled in the normal way and willreduce the risk of infection to a minimum.

The subject of the invention is an implant with antibiotic orantimicrobial long-term action, in particular a vascular prosthesis,with a basic structure which defines the form of the implant and whichis made of substantially non-absorbable or only slowly absorbablepolymer material and of a coating of an absorbable material, with alayer of metallic silver situated on the polymer material and underneaththe coating.

It was to be feared that an interaction would take place between theabsorbable coating and the silver layer. This is also actually the caseespecially when the absorbable layer is made of biological material suchas gelatin and collagen. However, it was found that this interaction israther of advantage. Thus, as will be explained in more detail below,comparative tests have shown that the release of silver ions inprostheses provided with an absorbable layer is initially very highcompared to prostheses provided only with a silver layer, even when nosilver was incorporated in the absorbable layer. The silver layer isevidently corroded by the constituents of the absorbable layer, whichcan occur during storage of the prosthesis up to the time it is used.Released silver ions deposit in the absorbable layer and, as the latterbreaks down, are released more rapidly. If the silver layer is ofsufficient dimension, this does not impair the long-term action of thesilver layer, with the result that the bactericidal action of the silverlayer is maintained for a long time even when the absorbable layer isbroken up.

The silver layer advantageously adheres firmly to the surface of thepolymer material and is in particular anchored in it. This can beachieved using the vapor-deposition methods known from the prior art, inparticular the abovementioned IBAD technique. The silver layer istherefore preferably vapor-deposited onto the polymer surface. It isparticularly preferred if the silver atoms of the silver layer areimpressed into the polymer surface of the basic structure. This canadvantageously be done by bombarding the polymer surface with argonions, for example, during the vapor-deposition.

The silver layer covers the polymer surface at least at the locationswhere it comes into contact with connective tissue after implantation,and it preferably covers it completely. Closed silver layers are presentin particular at least in these areas. In the preferred embodiment, thesilver layer is of such thickness that in vivo, i.e. after implantation,it has a dwell time on the polymer surface of more than one year, inparticular of more than 2 years, and releases silver ions during thistime. It is particularly advantageous if the silver layer is of suchthickness that, as it breaks down in the body, only about 5 to 10%, inparticular 7 to 8%, of the layer thickness is removed per annum. It hasin fact been found that the possible damage to the surrounding tissue,as described in the literature, is not a function of the layer thicknessof the silver layer. Thicker layers do not release more silver ions perunit of time, but as a result they release them for a longer period oftime. Layer thicknesses in the range of 1000 Å to 2500 Å have provenuseful, in particular those of ca. 1300 Å. Such layer thicknessesexhibit a good long-term action. The layer thickness can also be greaterand amount to as much as 4000 Å and over, but greater layer thicknessesdo not bring any real additional advantages. Smaller layer thicknessesmay, particularly because of the interaction with the absorbable layer,lead to an undesirably early attenuation of the long-term action.

The polymer material for the basic structure can be from the usualpolymers used in implants, in particular vascular prostheses, forexample polyester, polytetrafluoroethylene, polyurethane and, in specialcases, also polyamides, preference generally being given to polyester.The silver layer is preferably situated at least on the side or sides ofthe polymer material facing toward the connective tissue. The silverlayer is preferably composed of pure elemental silver.

The basic structure of the implant is porous, especially in the case ofa vascular prosthesis, but also in the case of hernia meshes, patchesand the like, and the absorbable layer is an impregnation which sealsoff the pores of the implant. As has already been mentioned above, theabsorbable layer can be formed from biological material which, ifappropriate, can be crosslinked. Possible materials are, in particular,collagen, gelatin and albumin. Alternatively, or in combination, theabsorbable layer can also be made from synthetic polymers and copolymerswhich are degradable or absorbable in vivo. In addition to at leastpartially water-soluble polymers such as polyvinyl alcohol andcarboxymethylcellulose, these mainly include the polymers and copolymersof hydroxy acids. In this context, these are in particular polymers andcopolymers of glycolide, lactide, ε-caprolactone, trimethylcarbonate andparadioxanone. It is also possible to use mixtures of the polymers. Bysuitable choice of the polymers, the desired duration of absorption canbe set. This is preferably within 4 months and in particular within 40days. Such a time is expedient since, depending on the type ofprosthesis, the impregnating action is no longer necessary during thistime because of the ingrowing connective tissue.

The coating of absorbable material, which in the case of a flat implantcan be provided on just one side or else on both sides and can also bemade of different materials depending on the intended application, canin turn contain active substances which are released into thesurroundings during the absorption period. These are mainly activesubstances other than silver, for example antibiotics with a particularspectrum of action, or growth factors, active substances with hormonalaction, and so on.

A porous basic structure is particularly advantageously made from atextile material, as is the case for example in vascular prostheses andhernia meshes. Suitable materials are formed-loop knits, drawn-loopknits, braids, wovens and nonwovens, preference usually being given toformed-loop knits. It is also possible to use combinations of thetextile structures, for example formed-loop knits which have a nonwovencover layer. Porous sintered material, such as expandedpolytetrafluororethylene, can also be used as polymer material, and thisis a frequently used polymer material especially for vascularprostheses.

The silver layer is preferably a closed silver layer. However, this doesnot mean that the pores in the case of a porous vascular structure aresealed off by the silver layer. Rather, the silver layer adapts to thesurface structure of the polymer material so that the pores retain theiroriginal shape and size. This applies for expandedpolytetrafluoroethylene in the same way as for textile fiber material.In the case of fiber material, the fiber surface is coated with silver.In the case of textile fiber material, it is possible to provide thefibers or yarns with the silver layer before the basic structure isformed from them. It suffices, however, for silver to be vapor-depositedonto the finished basic structure at the accessible and/or desiredlocations, since it is these locations which are exposed to the risk ofinfection and come into contact with the surrounding tissue.

Further features of the invention will be evident from the followingdescription of preferred embodiments in conjunction with the dependentclaims. The individual features of one embodiment can in each case berealized singly or severally.

EXAMPLE 1

Double-velour knitted prostheses of polyester are clamped in a rotatableclamp device so that they hang freely as a bundle of parallel tubes withspaces between them. The clamp device is introduced into a vacuumchamber suitable for carrying out the IBAD technique, the vascularprostheses being vapor-deposited with silver and at the same timebombarded with argon ions. The coating operation is conducted until asilver layer thickness of 1300 Å is reached on the outside of thevascular prostheses or the fibers located there. If so desired, aprimary coating can be effected by vapor-deposition of other metals.Silver is also forced into the pores or interstices between the fibersof the vascular prostheses, so that the fiber surfaces are coated atthese locations too. However, the layer thickness is less there becauseof the “shadow effect” in the vapor-deposition.

The vascular prostheses coated in this way are removed from the clampdevice and then impregnated in the usual manner with absorbable materialat least on their outside, sealing off the porous structure. Thisimpregnation can be done in the usual way with collagen, in whichpartial crosslinking with glutaraldehyde is effected. Preference isgiven to a likewise known coating with gelatin which is crosslinked withdiisocyanate. As has been mentioned, bioactive substances can beintroduced into the coating solution in order to develop the biologicalactivity during the later absorption of the layer.

Determination of the amount of silver on the vascular prostheses (stillwithout absorbable layer) has revealed that the proportion of silverrelative to the total weight of the metallized prosthesis lies in therange of from 0.4 to 0.8% by weight. The proportion of silver dependsinter alia on the porosity of the basic structure of the vascularprosthesis. Close-knitted structures have a lower percentage proportionof silver than more porous structures. Moreover, the penetration of theporous implant with silver can be influenced by the way in which themethod is carried out, for example by moving the implants duringvapor-deposition, by guiding the streams of vapor and gas in aparticular way, etc. If, for example, an inner coating of tubularprostheses with silver is also desired, silver vapor can also flowthrough the inside of the prostheses during the coating operation.Turning the prosthesis round prior to a repeated vapor-deposition alsoleads to an inner coating.

Comparison Test

A vascular prosthesis according to Example 1, but not yet provided withthe absorbable impregnation layer, was placed in phosphate buffer (pH7.4) at 37° C.; the phosphate buffer was changed daily and the silvercontent in the previous phosphate buffer sample was determined. The testextended across a period of 365 days. The silver content in the removedphosphate buffer was initially 35 microgram/l and then fell rapidly, andthen after 50 days slowly (15 microgram/l), and after 365 days it wasca. 5 microgram/l.

Under the same conditions, a vascular prosthesis according to Example 1was examined which was coated with an absorbable impregnation layer ofgelatin crosslinked with diisocyanate. Although no silver was added tothe gelatin, a high content of silver in the range of ca. 70 to 80microgram/l was initially found in the phosphate buffer, and although itdecreased slightly it remained high until the absorbable layer hadlargely broken up. It was not until after about 50 days that the silvercontent in the phosphate buffer had fallen to the level shown after 50days by the vascular prosthesis not provided with the impregnationcoating, after which time the release of the silver ions into thephosphate buffer was essentially the same as in the vascular prosthesiswithout impregnation coating.

This comparison shows that the silver layer was attacked via theimpregnation coating, and silver ions were released into theimpregnation coating, and these then entered the phosphate buffer at anincreased rate and in increased number. The vascular prosthesis providedwith the impregnation layer thereafter showed a comparable release ofsilver ions, which means that the initial strong release of silver hasno negative effect on the long-term action.

Tissue Reaction

Vascular prostheses produced in a similar way, but with silver layers of1600 Å and 2500 Å, were implanted in rats, rabbits and pigs. Uponexplantation after 3 months and 6 months, good integration was found.All the implants showed no abnormal findings. The internal organs tooshowed no abnormal findings. There were no signs of chronic inflammatoryreactions.

Artificial Infection

A comparison was conducted using implants according to the invention,and implants which, instead of having a silver layer on the basicstructure, contained silver acetate incorporated in the absorbablecoating. The comparison specimens were artificially infected withproblem microbes and implanted in rabbits. They were explanted after 7days. The comparison specimens were then incubated for 48 hours in CASObroth, after which a microbial count was conducted. The microbialcolonization was determined microbiologically in 36 specimens. It wasfound that, in the implants according to the invention, only 22%, i.e. 8implants, were colonized with a small number of microbes, whereas, inthe implants with silver acetate in the absorbable coating, infectionwas found in 67%, corresponding to 23 implants.

1-17. (canceled)
 18. Prosthesis for replacement of hollow organs withantibiotic long-term action with a basic structure which defines theform of the prosthesis and which is made of substantially non-absorbableor only slowly absorbable polymer material and of a coating of anabsorbable material, with a layer of metallic silver situated on thepolymer material and underneath the coating.
 19. The prosthesis asclaimed in claim 18, wherein the silver layer adheres firmly on thepolymer material.
 20. The prosthesis as claimed in claim 18, wherein thesilver layer is vapor-deposited onto the polymer surface.
 21. Theprosthesis as claimed in claim 18, wherein silver atoms of the silverlayer are impressed into the polymer surface of the basic structure. 22.The prosthesis as claimed in claim 18, wherein the silver layer is asubstantially closed layer.
 23. The prosthesis as claimed in claim 18,wherein the silver layer is of such thickness that, as it breaks down inthe body, a maximum of about 5 to 10% of the layer is removed per annum.24. The prosthesis as claimed in claim 18, wherein the silver layer hasa layer thickness of 2500 to 1000 Å.
 25. The prosthesis as claimed inclaim 18, wherein the silver layer is composed exclusively of elementalsilver.
 26. The prosthesis as claimed in claim 18, wherein the basicstructure is porous, the silver layer leaves the pores open, and theabsorbable layer is an impregnation which seals the pores of theprosthesis.
 27. The prosthesis as claimed in claim 18, wherein theabsorbable coating is formed from optionally crosslinked biologicalmaterial.
 28. The prosthesis as claimed in claim 18, wherein theabsorbable coating is made of synthetic polymers and copolymers whichare absorbable in vivo.
 29. The prosthesis as claimed in claim 18,wherein the composition of the absorbable coating is chosen such that itis absorbed at the latest after four months.
 30. The prosthesis asclaimed in claim 18, wherein the coating of absorbable material in turncontains active substances which are released during absorption of theabsorbable coating.
 31. The prosthesis as claimed in claim 18, whereinthe basic structure is made from a textile material.
 32. The prosthesisas claimed in claim 31, wherein the fibers of the textile basicstructure are coated with silver at least at the locations which pointtoward at least one surface of the prosthesis.
 33. The prosthesis asclaimed in claim 32, wherein substantially the entire surface of thefibers being coated with silver.
 34. The prosthesis as claimed in claim18, wherein the basic structure is made from a sintered material. 35.The prosthesis as claimed in claim 18, wherein said implant is designedas a vascular prosthesis.